The treatment and cure of cancer remains one of the greatest challenges of modern medicine. The war on cancer first began with the use of surgical strategies and radiation therapy. However, the general inability of these early approaches to eradicate metastatic cancers revealed a need for alternative tactics. As a result, small molecule- and macromolecular-based chemotherapeutic compounds have become an essential element in today's anticancer arsenal.
Prompted by the unwanted side effects of many oncolytic drugs, and inspired by Ehrlich's original concept of the ‘magic bullet’, contemporary anticancer drug development has focused on enhancing drug selectivity and specificity through two main strategies—molecular target-based cancer chemotherapy (often referred to as ‘targeted therapy’) and the use of molecular targeting techniques.
Molecular target-based therapies are based on an in-depth understanding of cancer cell biology. Such drugs are designed to act upon molecular targets specific to a tumor. Despite some of the early successes of targeted therapies, their clinical development has exposed unwanted adverse effects including thrombocytopenia, myelosuppression, hypertension, neutropenia, myalgia, edema, cardiotoxicity and pulmonary toxicity.
Molecular targeting techniques generally provide specificity via tumor-selective binding or uptake of drug conjugates as mediated by tumor-specific surface epitopes or transporters. Anticancer molecular targeting strategies employ an extensive array of small molecule- (e.g., folates, carbohydrates, peptides) or macromolecule- (e.g., monoclonal antibodies) conjugates and can provide specificity on an intracellular compartmental-, specific cell-type- and/or even at the whole organ-level. Examples include the oligopeptide transporter-mediated uptake of bestatin, the folate receptor-based enhancement of tumor specificity of folate-anticancer drugs, and the ability of organic anion transporters to boost hepatic uptake of anticancer-bile acid drug conjugates.
While molecular-targeted drugs have displayed both successes and limitations, a notable advantage of identifying a successful molecular targeting modality is its potential general applicability to a wide range of therapeutic agents (i.e., a successful tumor-directing small molecule can be conjugated to a variety of anticancer agents to enhance their tumor-specificity). Thus, molecular-targeting techniques offer a greater likelihood to develop broadly applicable platforms for modulating the selectivity, specificity, absorption, distribution, metabolism and excretion of a wide range of anticancer agents (including both conventional cytotoxics/cytostatics as well as newer targeted therapies).
Chemoenzymatic glycorandomization employs the inherent or engineered substrate promiscuity of sugar-activating enzymes, coupled with inherently promiscuous natural product glycosyltransferases (GTs), to provide a robust chemoenzymatic means to glycodiversify natural product-based scaffolds. Chemoenzymatic glycorandomization has been successfully applied toward antibiotic scaffolds (novobiocin, erythromycin/megalomicin, vancomycin), anticancer models (rebeccamycin/staurosporine/AT2433 and calicheamicin) and antihelmenthics (avermectin/ivermectin).
In contrast, neoglycorandomization relies upon the installation of a uniquely reactive methoxyamine ‘handle’ followed by a direct reaction with free sugars. Neoglycorandomization is a groundbreaking advance over classical chemical glycosylation strategies (which require extensive steps for sugar/aglycon protection/deprotection and sugar activation) and allows for extensive neoglycorandomized natural product libraries in essentially a single step.
While enzymatic glycorandomization is restricted to the inherent specificity of the natural GTs employed, neoglycorandomization can be accomplished essentially anywhere the methoxyamine handle can be installed. This allows one to expand beyond natural positions of glycosylation to explore the potential benefits of glycosylating even non-glycosylated natural products and therapeutics.
Therefore, a need exists for compositions and methods for rapidly identifying and assessing compounds which can enhance the tumor-specific uptake of drug-conjugates.